The Gut–Liver Axis Mediates Liver Injury Induced by Low-Molecular-Weight Polycyclic Aromatic Hydrocarbons Through TLR4-Dependent Inflammation and Bile Acid Dysregulation

Low-molecular-weight polycyclic aromatic hydrocarbons (LMW-PAHs) are ubiquitous dietary contaminants in grilled, smoked, and thermally processed foods, yet their hepatotoxic mechanisms remain poorly understood. We established a rat model co-exposed to fluorene (Flu) and phenanthrene (Phe) at low, medium, and high doses, validated by urinary metabolites and colonic AHR/CYP1A1. We assessed colonic barrier integrity, gut microbiota (GM) composition, lipopolysaccharide (LPS) translocation, hepatic inflammation, oxidative stress, lipid metabolism, and gut–liver metabolomic profiles. Flu/Phe co-exposure reduced tight junction proteins and altered GM composition—characterized by increased Gram-negative bacteria and reduced gut health indices—facilitating LPS translocation and upregulating the hepatic TLR4/MyD88/NLRP3 signaling axis, which was associated with inflammation, oxidative stress, and lipid metabolic disorders. The medium-dose group exhibited the most pronounced effects, suggesting a possible non-monotonic dose–response relationship. Metabolomic analysis revealed bile secretion as the most significantly enriched pathway common to colon and liver. Mechanistically, combined Flu/Phe exposure disrupted bile acid homeostasis by suppressing FXR/SHP while upregulating CYP7A1 and CYP8B1. Collectively, these findings demonstrate that LMW-PAHs induce liver injury through two distinct mechanisms: GM dysbiosis-driven LPS/TLR4 signaling and FXR/SHP-mediated bile acid dysregulation. The gut–liver axis thus provides candidate molecular nodes for LMW-PAH dietary risk assessment, though validation at dietary-relevant doses is required given the high-dose mechanistic design of this study.